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Drug interaction of thalidomide with midazolam and other compounds : heterotropic cooperativiy of human cyochrome P450

Research Project

Project/Area Number 21590177
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionShowa Pharmaceutical University

Principal Investigator

MURAYAMA Norie  昭和薬科大学, 薬学部, 講師 (90219949)

Co-Investigator(Kenkyū-buntansha) YAMAZAKI Hiroshi  昭和薬科大学, 薬学部, 教授 (30191274)
SHIMIZU Makiko  昭和薬科大学, 薬学部, 助教 (90307075)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords薬物相互作用 / サリドマイド / 協同性 / ヒト型モデルマウス / P450 / HepaRG / チトクロムP450 / CYP3A4 / GSH / CYP3A / 促進定数 / ミダゾラム水酸化活性
Research Abstract

There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450(P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by thalidomide in a dose-dependent manner. Unexpected drug interactions involving thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.We investigate these drug interactions in cultured human liver cell line system more closely resembled livers. A new hepatic cell line system with differentiated HepaRG cryopreserved(Biopredic International, Rennes, France) was adopted. These results suggest that cultured human cell line system with differentiated HepaRG cryopreserved could be applicable to thalidomide drug interaction study. Further oxidative metabolism of 5-hydoroxythalidomide to 5-hydroxythalidomide GSH-conjugate formation is under investigation using the new HepaRG cell system mimicking in vivo human livers.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (47 results)

All 2012 2011 2010 2009 Other

All Journal Article (29 results) (of which Peer Reviewed: 29 results) Presentation (14 results) Remarks (4 results)

  • [Journal Article] Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system2011

    • Author(s)
      Nakamura, K., Mizutani, R., Sanbe, A., Enosawa, S., Kasahara, M., Nakagawa, A., Ejiri, Y., Murayama, N., Miyamoto, Y., Torii, T., Kusakawa, S., Yamauchi, J., Fukuda, M., Yamazaki, H., and Tanoue. A
    • Journal Title

      J. Biosci. Bioeng

      Volume: 111 Pages: 78-84

    • NAID

      110008440354

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants2011

    • Author(s)
      Akiyoshi, T. Saito, T., Murase, S., Miyazaki, M. Murayama, N., Yamazaki, H., Guengerich, F. P., Nakamura, K., Yamamoto, K., and Ohtani, H
    • Journal Title

      Drug Metab. Dispos

      Volume: 39 Issue: 4 Pages: 724-728

    • DOI

      10.1124/dmd.110.036780

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Species d ifference between cynomolgus monkeys and humans on cytochromes P450 2D and 3A-dependent drug oxidation activities in liver microsomes2011

    • Author(s)
      Emoto, C., Iwasaki, K., Koizumi, R., Utoh, M., Murayama, N., Uno Y., and Yamazaki, H
    • Journal Title

      J. Health Sci

      Volume: 57 Pages: 164-170

    • NAID

      130000663115

    • URL

      http://dx.doi.org/10.1248/jhs.57.164

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Sorafenib and sunitinib, two anti-cancer drugs, inhibit CYP3A4-and activate CYP3A5-mediated midazolam 1' hydroxylation2011

    • Author(s)
      Sugiyama, M., Fujita, K., Murayama, N., Akiyama, Y., Yamazaki, H., and Sasaki, Y
    • Journal Title

      Drug Metab. Dispos

      Volume: 39 Issue: 5 Pages: 757-762

    • DOI

      10.1124/dmd.110.037853

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Human liver enzymes responsible for metabolic elimination of tyramine, a vasopressor agent from daily food2011

    • Author(s)
      Niwa, T., Murayama, N., Umeyama, H., Shimizu, M., and Yamazaki, H
    • Journal Title

      Drug Metab. Lett

      Volume: 5 Pages: 216-219

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol with regard to CYP2B6 and UGT1A9 genotype and patient age2011

    • Author(s)
      Kansaku F, Kumai T, Sasaki K, Yokozuka M, Shimizu M, Tateda T, Murayama N, Kobayashi S, Yamazaki H
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 26 Pages: 532-7

    • NAID

      130004463217

    • URL

      http://dx.doi.org/10.2133/dmpk.DMPK-11-RG-039

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Stereoselectivity of human cytochrome p450 in metabolic and inhibitory activities2011

    • Author(s)
      Niwa T, Murayama N, Yamazaki H
    • Journal Title

      Curr Drug Metab

      Volume: 12 Pages: 549-69

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition2011

    • Author(s)
      Niwa T, Murayama N, Yamazaki H
    • Journal Title

      Curr Drug Metab

      Volume: 12 Pages: 412-35

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] CYP2G2, pseudogenized in human, is expressed in nasal mucosa of cynomolgus monkey and encodes a functional drug-metabolizing2011

    • Author(s)
      Uno Y, Uehara, S., Murayama, N., Yamazaki, H.
    • Journal Title

      Drug Metab.Dispos.

      Volume: 39 Issue: 4 Pages: 717-723

    • DOI

      10.1124/dmd.110.036574

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanism-based inhibition of cytochrome P450 (CYP) 2A6 by chalepensin in recombinant systems, in human liver microsomes and mice in vivo2011

    • Author(s)
      Ueng, Y.-F., Chen, C.-C., Chung, Y.-T, Liu, T.-Y., Chang, Y.-P., Lo, W.-S., Murayama, N., Yamazaki, H., Soucek, P., Chau, G.-Y., Chi, C.-W., Chen, R.-M., Li D.T.
    • Journal Title

      Brit.J.Pharmacol.

      Volume: 163 Issue: 6 Pages: 1250-1262

    • DOI

      10.1111/j.1476-5381.2011.01341.x

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In Vivo Formation of a Glutathione Conjugate Derived from Thalidomide in Humanized uPA-NOG2011

    • Author(s)
      Yamazaki, H., Suemizu, H.(8名・2番目)
    • Journal Title

      Mice Chem Res Toxicol

      Volume: 24 Issue: 3 Pages: 287-289

    • DOI

      10.1021/tx200005g

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human liver enzymes responsible for metabolic elimination of tyramine, a vasopressor agent from daily food2011

    • Author(s)
      Niwa, T., Murayama, N., Umeyama, H., Shimizu, M., Yamazaki, H.
    • Journal Title

      Drug Metab.Lett

      Volume: 5 Pages: 216-219

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Individual Differences in Pharmacokinetics and Pharmacodynamics of Anesthetic Agent Propofol with Regard to CYP2B6 and UGT1A9 Genotype and Patient Age2011

    • Author(s)
      Kansaku, F, Kumai, T., Sasaki, K., Yukozuka, M., Shimizu, M., Tateda, T., Murayama, N., Kobayashi, S., Yamazaki, H.
    • Journal Title

      Drug Metabolism and Pharmacokinetics

      Volume: 26 Issue: 5 Pages: 532-537

    • DOI

      10.2133/dmpk.DMPK-11-RG-039

    • NAID

      130004463217

    • ISSN
      1347-4367, 1880-0920
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunochemical detection of cytoclirome P450 enzymes in liver microsomes of 27 cynomolgus monkeys2011

    • Author(s)
      Uehara, S., Murayama, N., Nakanishi, Y., Zeldin, D.C., Yamazaki, H., Uno, Y.
    • Journal Title

      J.Pharmacol.Exp.Ther

      Volume: 339 Issue: 2 Pages: 654-661

    • DOI

      10.1124/jpet.111.185009

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Species difference between cynomolgus monkeys and humans on cytochromes P450 2D and 3A-dependent drug oxidation activities in liver microsomes.2011

    • Author(s)
      Emoto, C., Iwasaki, K., Koizumi, R., Utoh, M., Murayama, N., Uno Y., Yamazaki, H.
    • Journal Title

      J.Health Sci.

      Volume: 57 Pages: 164-170

    • NAID

      130000663115

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system.2011

    • Author(s)
      Nakamura, K., Mizutani, R., Sanbe, A., Enosawa, S., Kasahara, M., Nakagawa, A., Ejiri, Y., Murayama, N., Miyamoto, Y., Torii, T., Kusakawa, S., Yamauchi, J., Fukuda, M., Yamazaki, H., Tanoue.A.
    • Journal Title

      J.Biosci.Bioeng

      Volume: 111 Pages: 78-84

    • NAID

      110008440354

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.2011

    • Author(s)
      Akiyoshi, T.Saito, T., Murase, S., Miyazaki, M.Murayama, N.Yamazaki, H., Guengerich, F.P., Nakamura, K., Yamamoto, K., Ohtani, H
    • Journal Title

      Drug Metab.Dispos.

      Volume: 39 Pages: 74-728

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate2010

    • Author(s)
      Chowdhury, G., Murayama, N., Okada, Y., Uno, Y., Shimizu, M., Shibata, N., Guengerich, F. P., and Yamazaki, H
    • Journal Title

      Chem. Res. Toxicol

      Volume: 23 Pages: 1018-1024

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling2010

    • Author(s)
      Takano R, Murayama N, Horiuchi K, Kitajima M, Kumamoto M, Shono F, Yamazaki H
    • Journal Title

      Regul Toxicol Pharmacol

      Volume: 58 Pages: 252-8

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Structure-function relationships of inhibition of human cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives2010

    • Author(s)
      Shimada, T., Tanaka, K., Takenaka, T., Murayama, N., Martin, M. V., Foroozesh, M. K. Yamazaki, H., Guengerich, F. P, and Komori. M
    • Journal Title

      Chem. Res. Toxicol.

      Volume: 23 Issue: 12 Pages: 1921-1935

    • DOI

      10.1021/tx100286d

    • NAID

      130004639911

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate.2010

    • Author(s)
      Chowdhury, G.., Murayama, N., Okada, Y., Uno, Y., Shimizu, M., Shibata, N., Guengerich, F.P., Yamazaki, H.
    • Journal Title

      Chem.Res.Toxicol.

      Volume: 23 Pages: 1018-1024

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blood concentrations of 1, 4-dioxane in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling.2010

    • Author(s)
      Takano, R., Murayama, N., Horiuchi, K., Kitajima, M., Shono F., Yamazaki, H..
    • Journal Title

      J.Health Sci.

      Volume: 56 Pages: 557-565

    • NAID

      130000425091

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice.2010

    • Author(s)
      Yamazaki, H., Suemizu, H., Igaya, S., Shimizu, M., Shibata, N., Nakamura, M., Chowdhury, G., Guengerich, F.P.
    • Journal Title

      Chem.Res.ToxicoL

      Volume: 24 Pages: 287-289

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of cytochrome P450 3A enzymes in cynomolgus monkeys and humans2010

    • Author(s)
      Iwasaki, K., Murayama, N., Koizumi, R., Uno, Y., Yamazaki, H.
    • Journal Title

      Drug Metab.Pharmacokinet. (印刷中)

    • NAID

      10027583437

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Utilization of estimated physicochemical properties as an integrated part of predicting hepatic clearance in the early drug discovery stage : The impact of plasma and microsomal binding2009

    • Author(s)
      Emoto, C., Murayama, N.Rostami-Hodjegan, A., Yamazaki, H.
    • Journal Title

      Xenobiotica 39

      Pages: 227-235

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cytochrome P450-dependent drug oxidation activity of liver microsomes from Microminipigs, a possible new animal model for humans in non-clinical studies2009

    • Author(s)
      Murayama, N., Kaneko, N., Horiuchi, K., Ohyama, K., Shimizu, M., Ito, K., Yamazaki, H
    • Journal Title

      Drug Metab.Pharmacokinet. 24

      Pages: 404-408

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reverse type I binding spectra of human cytochrome P450 1B1 induced by flavonoid, stilbene, pyrene, naphthalene, phenanthrene, and biphenyl derivatives that inhibit catalytic activity : A structure-function relationship study2009

    • Author(s)
      Shimada, T., Tanaka, K.Takenaka, S.Foroozesh, M.K., Murayama, N., Yamazaki, H., Guengerich, F.P., Komori, M.Murayama, N., Kaneko, N., Horiuchi, K., Ohyama, K., Shimizu, M., Ito, K., Yamazaki, H
    • Journal Title

      Chem.Res.Toxicol. 22

      Pages: 1325-1333

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of histidine-tag on recombinant human cytochrome P450 3A5 catalytic activity in reconstitution systems2009

    • Author(s)
      Emoto, C., Murayama, N., Wakiya, S., Yamazaki, H.
    • Journal Title

      Drug Metab.Lett.t. 3

      Pages: 207-211

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oxidation of endobiotics mediated by xenobiotic-metabolizing forms of human cytochrome P4502009

    • Author(s)
      Niwa, T., Murayama, N., Yamazaki, H.
    • Journal Title

      Curr.Drug Metab. 10

      Pages: 700-712

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] チオカルバメート系除草剤モリネートの代謝消失における種差の検討2012

    • Author(s)
      村山典恵、山下真直、塚田藍、末水洋志、中村雅登、高野良治、清水万紀子、山崎浩史
    • Organizer
      日本薬学会第132回年会
    • Place of Presentation
      札幌
    • Year and Date
      2012-03-29
    • Related Report
      2011 Final Research Report
  • [Presentation] チオカルバメート系除草剤モリネートの代謝消失における種差の検討2012

    • Author(s)
      村山典恵、山下真直、塚田藍、高野良治、末水洋志、中村雅登、清水万紀子、山崎浩史
    • Organizer
      日本薬学会第132年会
    • Place of Presentation
      札幌市・北海道大学・高等教育推進機構
    • Year and Date
      2012-03-28
    • Related Report
      2011 Annual Research Report
  • [Presentation] Drug Metabolism In Human Hepatoma Cell Line System with Differentiated HepaRG Cryopresorved2011

    • Author(s)
      Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, Hiroshi Yamazaki
    • Organizer
      JSSX
    • Place of Presentation
      広島市・国際会議場
    • Year and Date
      2011-11-22
    • Related Report
      2011 Annual Research Report
  • [Presentation] Drug metabolism in human hepatomacell line system with differentiated HepaRG cryopreserved2011

    • Author(s)
      Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, and Hiroshi Yamazaki
    • Organizer
      26th JSSX Annual Meeting
    • Place of Presentation
      広島
    • Year and Date
      2011-11-17
    • Related Report
      2011 Final Research Report
  • [Presentation] Drug interactions of thalidomide with midazolam in human hepatoma cell line system with differentiated HepaRG cryopreserved2011

    • Author(s)
      Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, and Hiroshi Yamazaki
    • Organizer
      17 th North American regional ISSX meeting
    • Place of Presentation
      Atlanta, USA
    • Year and Date
      2011-10-18
    • Related Report
      2011 Final Research Report
  • [Presentation] Drug Interaction of Thalidomide with Midazolam in Human Hepatoma Cell Line System with Differentiated HepaRG Cryopreserved2011

    • Author(s)
      Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, Hiroshi Yamazaki
    • Organizer
      17^<th> Notth America ISSX Meeting
    • Place of Presentation
      Atranta, USA, Hotel Hirtone
    • Year and Date
      2011-10-17
    • Related Report
      2011 Annual Research Report
  • [Presentation] 肝試料画分を考慮した化学物質のヒト生理学的薬物動態モデルの精緻化2011

    • Author(s)
      村山典恵、國兼絵里子、塚田藍、高野良治、北島正人、清水万紀子、池田敏彦、山崎浩史
    • Organizer
      日本薬学会第131回年会
    • Place of Presentation
      静岡
    • Year and Date
      2011-03-29
    • Related Report
      2011 Final Research Report
  • [Presentation] 肝試料画分を考慮した化学物質のヒト生理学的薬物動態モデルの精緻化2011

    • Author(s)
      村山典恵、國兼絵里子、塚田藍、高野良治、北島正人、清水万紀子、山崎浩史
    • Organizer
      日本薬学会第131年会
    • Place of Presentation
      要旨集上にて発表
    • Year and Date
      2011-03-05
    • Related Report
      2010 Annual Research Report
  • [Presentation] An improved method to assess internal radiation exposure in humans using in vivo and in vitro animal pharmacokinetic data2010

    • Author(s)
      Toshihiko Ikeda, Norie Murayama and Hiroshi Yamazaki
    • Organizer
      25th JSSX Annual Meeting
    • Place of Presentation
      埼玉
    • Year and Date
      2010-10-08
    • Related Report
      2011 Final Research Report
  • [Presentation] Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol in patients genotyped for CYP2B6 and UGT1A92010

    • Author(s)
      Hiroshi Yamazaki, Toshio Kumai, Kuniharu Sasaki, Makito Yokozuka, Makiko Shimizu, Tadashi Tateda, Norie Murayama and Shinichi Kobayashi
    • Organizer
      ISSX Workshop on Genetic Polymorphisms in Drug Disposition
    • Place of Presentation
      Indianapolis, USA
    • Year and Date
      2010-04-11
    • Related Report
      2011 Final Research Report
  • [Presentation] ヒトと実験動物間で認められる薬物代謝酵素機能の種差2010

    • Author(s)
      村山典恵, 今村裕樹, 大久保真穂, 國兼絵里子, 松本史彦, 小野瀬優維, 佐々木国玄, 清水万紀子, 山崎浩史
    • Organizer
      日本薬学会第130回総会
    • Place of Presentation
      岡山
    • Year and Date
      2010-03-29
    • Related Report
      2009 Annual Research Report
  • [Presentation] Impact of genetic polymorphism of the CYP3A5 appeared in the metabolism of and inhibition by voriconazoke in a Japanese population2009

    • Author(s)
      村山典恵, 清水万紀子, 山崎浩史
    • Organizer
      日本薬物動態学会
    • Place of Presentation
      京都
    • Year and Date
      2009-11-27
    • Related Report
      2009 Annual Research Report
  • [Presentation] Impact of cytochrome p450 3A5 expression in human livers on drug interactions of anti-fungal agents with midazolam2009

    • Author(s)
      村山典恵, 中本美那子, 清水万紀子, 山崎浩史
    • Organizer
      16th International Conference on Cytochrome P450 ~Biochemistry, Biophysics, Biotechnology~
    • Place of Presentation
      沖縄
    • Year and Date
      2009-06-21
    • Related Report
      2009 Annual Research Report
  • [Presentation] Remarked properties of human cytochrome P450 1A2 and 3A5 in function and cooperativity for drug development2009

    • Author(s)
      山崎浩史
    • Organizer
      16th International Conference on Cytochrome P450 ~Biochemistry, Biophysics, Biotechnology~
    • Place of Presentation
      沖縄
    • Year and Date
      2009-06-21
    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://www.shoyaku.ac.jp/labosite/doutai/index.html

    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://www.shoyaku.ac.jp/labosite/doutai

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www.shoyaku.ac.jp/labosite/doutai/index.html

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.shoyaku.ac.jp/labosite/doutai/index.html

    • Related Report
      2009 Annual Research Report

URL: 

Published: 2009-04-01   Modified: 2016-04-21  

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